Happy Holidays to everyone, and wishing you all a healthier 2011.
Thursday, December 23, 2010
Tuesday, December 21, 2010
Study identifies prescription drugs associated with cases of violence
By Michael C. Cohen, president of the Institute for Safe Medication Practices
The link between violence and prescription drugs has rarely been studied. However, a study published last week in the journal PLoS ONE identified 31 drugs that are disproportionally associated with reported cases of violence.
The study drew on reports of violence and aggression made to the Food and Drug Administration from 2004 through the third quarter of 2009. While far from definitive, these findings signal that more research is needed.
Leading the list in numbers of reports is the smoking cessation drug Chantix (varenicline).
Also associated with violence were psychoactive medications for depression (Prozac and Paxil), attention deficit disorder (Strattera), and sedative/hypnotic drugs.
The authors, Thomas J. Moore, a consulting senior scientist at the Institute for Safe Medication Practices, Joseph Glenmullen of Harvard Medical School, and Curt D. Furberg of Wake Forest University School of Medicine, selected cases from the ISMP QuarterWatch database, which is composed of computer extracts of all adverse drug event reports received by FDA.
A violent event was defined as any case report mentioning homicide, physical assault, physical abuse, homicidal ideation or violence-related symptom.
For the five-year study period, the authors identified 484 drugs that accounted for 780,169 serious adverse event reports of all kinds. This total included 1,937 (0.25 percent) cases that met the violence criteria.
Thirty-one drugs met study criteria for a disproportionate association with violence, accounting for 1,527 (79 percent) of the violence cases.
Included were 387 reports of actual homicide, 404 that were physical assaults, 223 cases with violence-related symptoms, and 896 homicidal ideation reports.
The prominence of Chantix was not a surprise. An association between that drug and serious psychiatric symptoms, including hostile behavior, was also a finding in a 2008 study by our group that looked at FDA adverse event reports in the fourth quarter of 2007. The authors of the present study had earlier linked Chantix to thoughts and acts of aggression/violence. The association also led FDA to require product label changes, including a boxed warning for the drug.
The authors conclude that their data "provide new evidence" that violent acts are "associated with a relatively small group of drugs" and that systematic studies "are needed to establish the incidence, confirm differences among drugs and identify additional common features."
Read more: http://www.philly.com/inquirer/magazine/20101220_Check_Up.html
By Michael C. Cohen, president of the Institute for Safe Medication Practices
The link between violence and prescription drugs has rarely been studied. However, a study published last week in the journal PLoS ONE identified 31 drugs that are disproportionally associated with reported cases of violence.
The study drew on reports of violence and aggression made to the Food and Drug Administration from 2004 through the third quarter of 2009. While far from definitive, these findings signal that more research is needed.
Leading the list in numbers of reports is the smoking cessation drug Chantix (varenicline).
Also associated with violence were psychoactive medications for depression (Prozac and Paxil), attention deficit disorder (Strattera), and sedative/hypnotic drugs.
The authors, Thomas J. Moore, a consulting senior scientist at the Institute for Safe Medication Practices, Joseph Glenmullen of Harvard Medical School, and Curt D. Furberg of Wake Forest University School of Medicine, selected cases from the ISMP QuarterWatch database, which is composed of computer extracts of all adverse drug event reports received by FDA.
A violent event was defined as any case report mentioning homicide, physical assault, physical abuse, homicidal ideation or violence-related symptom.
For the five-year study period, the authors identified 484 drugs that accounted for 780,169 serious adverse event reports of all kinds. This total included 1,937 (0.25 percent) cases that met the violence criteria.
Thirty-one drugs met study criteria for a disproportionate association with violence, accounting for 1,527 (79 percent) of the violence cases.
Included were 387 reports of actual homicide, 404 that were physical assaults, 223 cases with violence-related symptoms, and 896 homicidal ideation reports.
The prominence of Chantix was not a surprise. An association between that drug and serious psychiatric symptoms, including hostile behavior, was also a finding in a 2008 study by our group that looked at FDA adverse event reports in the fourth quarter of 2007. The authors of the present study had earlier linked Chantix to thoughts and acts of aggression/violence. The association also led FDA to require product label changes, including a boxed warning for the drug.
The authors conclude that their data "provide new evidence" that violent acts are "associated with a relatively small group of drugs" and that systematic studies "are needed to establish the incidence, confirm differences among drugs and identify additional common features."
Read more: http://www.philly.com/inquirer/magazine/20101220_Check_Up.html
Friday, December 17, 2010
Buzzword "anti-oxidants" for the recent few years is holding pace. Some studies have shown that taking antioxidants can turn pro oxidants. The biochemistry is complex and complicated and further studies are needed for evaluation. So far, free radicals theories remain unconvincing, some are purely hypothetical based on conjecture. Caloric Restriction research shows promise, although its difficult to evaluate, since, it involves measuring life span of primates (non humans).
Few studies discuss the balance between "moping" up excess free radicals and upsetting biochemistry balance of free radicals, or if taking long term anti oxidants therapy, how would the body's natural defense cope under physiological stress? Its role in preventing further oxidization, or halting/reversing inflammation process?
Oxidative DNA damage preventive activity and antioxidant potential of plants used in Unani system of medicine
Mehar DARUKHSHAN Kalim email, Dipto Bhattacharyya email, Anindita Banerjee email and Sharmila Chattopadhyay email
BMC Complementary and Alternative Medicine 2010, 10:77doi:10.1186/1472-6882-10-77
Published: 16 December 2010
Abstract (provisional)
Background
There is increasing recognition that many of today's diseases are due to the "oxidative stress" that results from an imbalance between the formation and neutralization of reactive molecules such as reactive oxygen species (ROS) and reactive nitrogen species (RNS), which can be removed with antioxidants. The main objective of the present study was to evaluate the antioxidant activity of plants routinely used in the Unani system of medicine. Several plants were screened for radical scavenging activity, and the ten that showed promising results were selected for further evaluation.
Methods
Methanol (50%) extracts were prepared from ten Unani plants, namely Cleome icosandra, Rosa damascena, Cyperus scariosus, Gardenia gummifera, Abies pindrow, Valeriana wallichii, Holarrhena antidysenterica, Anacyclus pyrethrum, Asphodelus tenuifolius and Cyperus scariosus, and were used to determine their total phenolic, flavonoid and ascorbic acid contents, in vitro scavenging of DPPH * , ABTS * +, NO, * OH, O2.- and ONOO, and capacity to prevent oxidative DNA damage. Cytotoxic activity was also determined against the U937 cell line.
Results
IC50 values for scavenging DPPH * , ABTS * +, NO, * OH, O2.- and ONOO were in the ranges 0.007+/- 0.0001 - 2.006 +/- 0.002 mg/ml, 2.54 +/- 0.04 - 156.94 +/- 5.28 mug/ml, 152.23 +/- 3.51 - 286.59 +/- 3.89 mug/ml, 18.23 +/- 0.03 - 50.13 +/- 0.04 mug/ml, 28.85 +/- 0.23 - 537.87 +/- 93 mug/ml and 0.532 +/- 0.015 - 3.39 +/- 0.032 mg/ml, respectively. The total phenolic, flavonoid and ascorbic acid contents were in the ranges 62.89 +/- 0.43 -166.13 +/- 0.56 mg gallic acid equivalent (GAE)/g extract, 38.89 +/- 0.52 - 172.23 +/- 0.08 mg quercetin equivalent (QEE)/g extract and 0.14 +/- 0.09 - 0.98 +/- 0.21 mg AA/g extract. The activities of the different plant extracts against oxidative DNA damage were in the range 0.13-1.60 ug/ml. Of the ten selected plant extracts studied here, seven - C. icosandra, R. damascena, C. scariosus, G. gummifera, A. pindrow, V. wallichii and H. antidysenterica - showed moderate antioxidant activity. Finally, potentially significant oxidative DNA damage preventive activity and antioxidant activity were noted in three plant extracts: C. icosandra, R. damascena and C. scariosus. These three plant extracts showed no cytotoxic activity against U937 cells.
Conclusions
The 50% methanolic extracts obtained from different plant parts contained significant amounts of polyphenols with superior antioxidant activity as evidenced by the scavenging of DPPH * , ABTS * +, NO, * OH, O2.- and ONOO. C. icosandra, R. damascena and C. scariosus showed significant potential for preventing oxidative DNA damage and radical scavenging activity, and the G. gummifera, A. pindrow, V. wallichii, H. antidysenterica, A. pyrethrum, A. tenuifolius and O. mascula extracts showed moderate activity. The extracts of C. icosandra, R. damascena and C. scariosus showed no cytotoxicity against U937 cells. In conclusion, these routinely used Unani plants, especially C. icosandra, R. damascena and C. scariosus, which are reported to have significant activity against several human ailments, could be exploited as potential sources of natural antioxidants for plant-based pharmaceutical industries.
Few studies discuss the balance between "moping" up excess free radicals and upsetting biochemistry balance of free radicals, or if taking long term anti oxidants therapy, how would the body's natural defense cope under physiological stress? Its role in preventing further oxidization, or halting/reversing inflammation process?
Oxidative DNA damage preventive activity and antioxidant potential of plants used in Unani system of medicine
Mehar DARUKHSHAN Kalim email, Dipto Bhattacharyya email, Anindita Banerjee email and Sharmila Chattopadhyay email
BMC Complementary and Alternative Medicine 2010, 10:77doi:10.1186/1472-6882-10-77
Published: 16 December 2010
Abstract (provisional)
Background
There is increasing recognition that many of today's diseases are due to the "oxidative stress" that results from an imbalance between the formation and neutralization of reactive molecules such as reactive oxygen species (ROS) and reactive nitrogen species (RNS), which can be removed with antioxidants. The main objective of the present study was to evaluate the antioxidant activity of plants routinely used in the Unani system of medicine. Several plants were screened for radical scavenging activity, and the ten that showed promising results were selected for further evaluation.
Methods
Methanol (50%) extracts were prepared from ten Unani plants, namely Cleome icosandra, Rosa damascena, Cyperus scariosus, Gardenia gummifera, Abies pindrow, Valeriana wallichii, Holarrhena antidysenterica, Anacyclus pyrethrum, Asphodelus tenuifolius and Cyperus scariosus, and were used to determine their total phenolic, flavonoid and ascorbic acid contents, in vitro scavenging of DPPH * , ABTS * +, NO, * OH, O2.- and ONOO, and capacity to prevent oxidative DNA damage. Cytotoxic activity was also determined against the U937 cell line.
Results
IC50 values for scavenging DPPH * , ABTS * +, NO, * OH, O2.- and ONOO were in the ranges 0.007+/- 0.0001 - 2.006 +/- 0.002 mg/ml, 2.54 +/- 0.04 - 156.94 +/- 5.28 mug/ml, 152.23 +/- 3.51 - 286.59 +/- 3.89 mug/ml, 18.23 +/- 0.03 - 50.13 +/- 0.04 mug/ml, 28.85 +/- 0.23 - 537.87 +/- 93 mug/ml and 0.532 +/- 0.015 - 3.39 +/- 0.032 mg/ml, respectively. The total phenolic, flavonoid and ascorbic acid contents were in the ranges 62.89 +/- 0.43 -166.13 +/- 0.56 mg gallic acid equivalent (GAE)/g extract, 38.89 +/- 0.52 - 172.23 +/- 0.08 mg quercetin equivalent (QEE)/g extract and 0.14 +/- 0.09 - 0.98 +/- 0.21 mg AA/g extract. The activities of the different plant extracts against oxidative DNA damage were in the range 0.13-1.60 ug/ml. Of the ten selected plant extracts studied here, seven - C. icosandra, R. damascena, C. scariosus, G. gummifera, A. pindrow, V. wallichii and H. antidysenterica - showed moderate antioxidant activity. Finally, potentially significant oxidative DNA damage preventive activity and antioxidant activity were noted in three plant extracts: C. icosandra, R. damascena and C. scariosus. These three plant extracts showed no cytotoxic activity against U937 cells.
Conclusions
The 50% methanolic extracts obtained from different plant parts contained significant amounts of polyphenols with superior antioxidant activity as evidenced by the scavenging of DPPH * , ABTS * +, NO, * OH, O2.- and ONOO. C. icosandra, R. damascena and C. scariosus showed significant potential for preventing oxidative DNA damage and radical scavenging activity, and the G. gummifera, A. pindrow, V. wallichii, H. antidysenterica, A. pyrethrum, A. tenuifolius and O. mascula extracts showed moderate activity. The extracts of C. icosandra, R. damascena and C. scariosus showed no cytotoxicity against U937 cells. In conclusion, these routinely used Unani plants, especially C. icosandra, R. damascena and C. scariosus, which are reported to have significant activity against several human ailments, could be exploited as potential sources of natural antioxidants for plant-based pharmaceutical industries.
Thursday, December 16, 2010
Several studies show vitamin B1 warding off kidney failure in diabetic patients*
other studies are showing similar benefits in slowing progression of heart failure and improves survival rates post myocardial infarct.
* Rabbani N, Alam, SS, Riaz S, et al. High-dose thiamine therapy for patients with type 2 diabetes and microalbuminuria: a randomised, double-blind placebo-controlled pilot study. Diabetologia. 2008 Dec 5.
Benfotiamine improves functional recovery of the infarcted heart via activation of pro-survival G6PD/Akt signaling pathway and modulation of neurohormonal response.
Katare R, Caporali A, Emanueli C, Madeddu P.
Bristol Heart Institute, University of Bristol, Bristol Royal Infirmary, Bristol, UK.
Abstract
Benfotiamine (BFT) is a transketolase activator that directs glucose to the pentose phosphate pathway. The present study investigated whether BFT improves the recovery after myocardial infarction (MI) and explored underlying mechanisms of protection. Non-diabetic and streptozotocin-induced type 1 diabetic mice were supplemented with BFT (70 mg/kg/day in drinking water) for 4 weeks and then subjected to MI or sham operation. Cardiac function was monitored by echocardiography. At two weeks post-MI, intra-ventricular pressure was measured by Millar tip-catheter and hearts were collected for biochemical, immunohistochemical and expressional analyses. No treatment effect was observed in sham-operated mice. Post-MI mortality was higher in diabetic mice and hemodynamic studies confirmed the worsening effect of diabetes on functional recovery. Furthermore, diabetic mice demonstrated increased cardiomyocyte apoptosis, reduced reparative angiogenesis, larger scars, enhanced oxidative stress, and blunted activation of the pro-survival VEGF receptor-2/Akt/Pim-1 signaling pathway. BFT improved post-MI survival, functional recovery and neovascularization and reduced cardiomyocyte apoptosis and neurohormonal activation in diabetic as well as in non-diabetic mice. In addition, BFT stimulated the activity of pentose phosphate pathway enzymes, leading to reduction of oxidative stress, phosphorylation/activation of VEGF receptor-2 and Akt and increased Pim-1, pBad and Bcl-2 levels. These effects were contrasted on silencing glucose-6-phosphate dehydrogenase, the key enzyme in pentose phosphate pathway, or inhibiting Akt. BFT benefits post-MI recovery through stimulation of pro-survival mechanisms and containment of neurohormonal response. These results may have implications for the treatment of myocardial ischemia.
other studies are showing similar benefits in slowing progression of heart failure and improves survival rates post myocardial infarct.
* Rabbani N, Alam, SS, Riaz S, et al. High-dose thiamine therapy for patients with type 2 diabetes and microalbuminuria: a randomised, double-blind placebo-controlled pilot study. Diabetologia. 2008 Dec 5.
Benfotiamine improves functional recovery of the infarcted heart via activation of pro-survival G6PD/Akt signaling pathway and modulation of neurohormonal response.
Katare R, Caporali A, Emanueli C, Madeddu P.
Bristol Heart Institute, University of Bristol, Bristol Royal Infirmary, Bristol, UK.
Abstract
Benfotiamine (BFT) is a transketolase activator that directs glucose to the pentose phosphate pathway. The present study investigated whether BFT improves the recovery after myocardial infarction (MI) and explored underlying mechanisms of protection. Non-diabetic and streptozotocin-induced type 1 diabetic mice were supplemented with BFT (70 mg/kg/day in drinking water) for 4 weeks and then subjected to MI or sham operation. Cardiac function was monitored by echocardiography. At two weeks post-MI, intra-ventricular pressure was measured by Millar tip-catheter and hearts were collected for biochemical, immunohistochemical and expressional analyses. No treatment effect was observed in sham-operated mice. Post-MI mortality was higher in diabetic mice and hemodynamic studies confirmed the worsening effect of diabetes on functional recovery. Furthermore, diabetic mice demonstrated increased cardiomyocyte apoptosis, reduced reparative angiogenesis, larger scars, enhanced oxidative stress, and blunted activation of the pro-survival VEGF receptor-2/Akt/Pim-1 signaling pathway. BFT improved post-MI survival, functional recovery and neovascularization and reduced cardiomyocyte apoptosis and neurohormonal activation in diabetic as well as in non-diabetic mice. In addition, BFT stimulated the activity of pentose phosphate pathway enzymes, leading to reduction of oxidative stress, phosphorylation/activation of VEGF receptor-2 and Akt and increased Pim-1, pBad and Bcl-2 levels. These effects were contrasted on silencing glucose-6-phosphate dehydrogenase, the key enzyme in pentose phosphate pathway, or inhibiting Akt. BFT benefits post-MI recovery through stimulation of pro-survival mechanisms and containment of neurohormonal response. These results may have implications for the treatment of myocardial ischemia.
Wednesday, December 15, 2010
Watch out for these drugs on the FDA monitoring list:
13 Drugs on Latest FDA List for Safety Monitoring
July 2, 2010 — A watch list of 13 drugs based on potential signs of serious risks or new safety information collected by the Adverse Event Reporting System (AERS) of the US Food and Drug Administration (FDA) during the first quarter of 2010 has been released.
The FDA is studying all of the drugs to determine the need for any regulatory action.
A drug's appearance on the watch list does not mean the agency has determined that the drug poses the health risk in question. Physicians should not stop prescribing the drug, and patients should not stop taking it, according to the FDA.
The FDA is evaluating 2 antibiotics — azithromycin (Zithromax; Pfizer) and clarithromycin (Biaxin; Abbott) — to find out whether they are associated with liver failure. Suspicions about azithromycin and liver failure are not new. The label for the antibiotic states that adverse events discovered after the drug entered the marketplace — and for which a causal relationship may not be established — include "abnormal liver function including hepatitis and cholestatic jaundice, as well as rare cases of hepatic necrosis and hepatic failure, some of which have resulted in death." During clinical trials, cholestatic jaundice was a rarely reported adverse effect.
Postmarketing adverse events for clarithromycin have included infrequent cases of sometimes severe, but usually reversible, hepatic dysfunction, including cholestatic hepatitis, with or without jaundice. There also have been rare and fatal cases of hepatic failure "associated with serious underlying diseases and/or concomitant medications," according to the drug label. Cholestatic jaundice did not emerge as an adverse effect in clinical trials.
Two other antibiotics made it on the latest watch list. AERS turned up reports of pyloric stenosis linked to azithromycin extended release 2 g (Zmax; Pfizer) and pulmonary eosinophilia and eosinophilic pneumonia linked to daptomycin (Cubicin; Cubist Pharmaceuticals).
FDA Studying Anticoagulant to Determine Whether It Causes Blood Clots
Three other medications on the watch list are in the cardiovascular camp. The anticoagulant prasugrel (Effient; Eli Lilly), is being watched on account of thrombotic thrombocytopenic purpura — a rare and life-threatening disorder that causes clots to form in small blood vessels throughout the body. The drug's label warns that this disorder emerged as an adverse effect during clinical trials. Heartwire recently reported that researchers continue to debate whether the medication increases the risk for cancer.
Another drug, dronedarone (Multaq; Sanofi-Aventis), used to treat atrial fibrillation and atrial flutter, has come under surveillance because of reports of congestive heart failure. As reported by Heartwire, clinicians have considered dronedarone a safer alternative to amiodarone (Cordarone; Wyeth-Ayerst; Pacerone; Upsher-Smith) for patients with atrial fibrillation.
The third cardiovascular drug on the watch list is ranolazine (Ranexa; Gilead), prescribed for patients with angina. Here, the FDA is investigating reports of torsades de pointes — a ventricular tachycardia that can lead to sudden death.
Two medications prescribed for narcolepsy — modafinil (Provigil; Cephalon) and sodium oxybate (Xyrem; Jazz Pharmaceuticals) — are under study for a possible association with convulsions. Physicians prescribe modafinil to counteract excessive sleepiness caused by narcolepsy, sleep apnea, or shift work. Likewise, sodium oxybate reduces daytime sleepiness, as well as the number of cataplexy attacks suffered, in patients with narcolepsy.
Perhaps the most well-known product on the watch list is the blend of estrogens marketed as Premarin (Wyeth), used to treat symptoms of menopause. It landed on the list based on reports of angioedema.
Potential Signals of Serious Risks/New Safety Information Identified by AERS, First Quarter 2010 http://www.medscape.com/viewarticle/724545?sssdmh=dm1.624895&src=nldne&uac=128675HJ
13 Drugs on Latest FDA List for Safety Monitoring
July 2, 2010 — A watch list of 13 drugs based on potential signs of serious risks or new safety information collected by the Adverse Event Reporting System (AERS) of the US Food and Drug Administration (FDA) during the first quarter of 2010 has been released.
The FDA is studying all of the drugs to determine the need for any regulatory action.
A drug's appearance on the watch list does not mean the agency has determined that the drug poses the health risk in question. Physicians should not stop prescribing the drug, and patients should not stop taking it, according to the FDA.
The FDA is evaluating 2 antibiotics — azithromycin (Zithromax; Pfizer) and clarithromycin (Biaxin; Abbott) — to find out whether they are associated with liver failure. Suspicions about azithromycin and liver failure are not new. The label for the antibiotic states that adverse events discovered after the drug entered the marketplace — and for which a causal relationship may not be established — include "abnormal liver function including hepatitis and cholestatic jaundice, as well as rare cases of hepatic necrosis and hepatic failure, some of which have resulted in death." During clinical trials, cholestatic jaundice was a rarely reported adverse effect.
Postmarketing adverse events for clarithromycin have included infrequent cases of sometimes severe, but usually reversible, hepatic dysfunction, including cholestatic hepatitis, with or without jaundice. There also have been rare and fatal cases of hepatic failure "associated with serious underlying diseases and/or concomitant medications," according to the drug label. Cholestatic jaundice did not emerge as an adverse effect in clinical trials.
Two other antibiotics made it on the latest watch list. AERS turned up reports of pyloric stenosis linked to azithromycin extended release 2 g (Zmax; Pfizer) and pulmonary eosinophilia and eosinophilic pneumonia linked to daptomycin (Cubicin; Cubist Pharmaceuticals).
FDA Studying Anticoagulant to Determine Whether It Causes Blood Clots
Three other medications on the watch list are in the cardiovascular camp. The anticoagulant prasugrel (Effient; Eli Lilly), is being watched on account of thrombotic thrombocytopenic purpura — a rare and life-threatening disorder that causes clots to form in small blood vessels throughout the body. The drug's label warns that this disorder emerged as an adverse effect during clinical trials. Heartwire recently reported that researchers continue to debate whether the medication increases the risk for cancer.
Another drug, dronedarone (Multaq; Sanofi-Aventis), used to treat atrial fibrillation and atrial flutter, has come under surveillance because of reports of congestive heart failure. As reported by Heartwire, clinicians have considered dronedarone a safer alternative to amiodarone (Cordarone; Wyeth-Ayerst; Pacerone; Upsher-Smith) for patients with atrial fibrillation.
The third cardiovascular drug on the watch list is ranolazine (Ranexa; Gilead), prescribed for patients with angina. Here, the FDA is investigating reports of torsades de pointes — a ventricular tachycardia that can lead to sudden death.
Two medications prescribed for narcolepsy — modafinil (Provigil; Cephalon) and sodium oxybate (Xyrem; Jazz Pharmaceuticals) — are under study for a possible association with convulsions. Physicians prescribe modafinil to counteract excessive sleepiness caused by narcolepsy, sleep apnea, or shift work. Likewise, sodium oxybate reduces daytime sleepiness, as well as the number of cataplexy attacks suffered, in patients with narcolepsy.
Perhaps the most well-known product on the watch list is the blend of estrogens marketed as Premarin (Wyeth), used to treat symptoms of menopause. It landed on the list based on reports of angioedema.
Potential Signals of Serious Risks/New Safety Information Identified by AERS, First Quarter 2010 http://www.medscape.com/viewarticle/724545?sssdmh=dm1.624895&src=nldne&uac=128675HJ
Corticosteroids are known to cause manic episodes, insomnia, and other CNS symptoms in many. This article concerns those who are using corticosteroids inhalers for asthma. Is it that helpful for asthma? There have been several articles warning about the dangers of beta2-agonists (LABAs) with corticosteroids. Later found to be of no benefits, (harmful), no longer advised for treating asthma. http://www.medicalnewstoday.com/articles/132495.php
Montelukast used to treat asthma has been linked to severe CNS reactions, including suicide ideation and self harm. http://www.leaderpost.com/news/Asthma+drug+linked+suicide+attempts+thoughts+self+harm/1768232/story.html
The article below, concerns inhaled corticosteroid and Diabetes Mellitus.
Inhaled Corticosteroid Use May Increase Risk for Diabetes Mellitus
Laurie Barclay, MD
December 15, 2010 — Inhaled corticosteroid use may increase the risk for diabetes mellitus, according to the results of a study reported in the November issue of the American Journal of Medicine.
"High doses of inhaled corticosteroids commonly used in patients with [chronic obstructive pulmonary disease (COPD)] are associated with an increase in the risk of requiring treatment for diabetes and of having to intensify therapy to include insulin," lead author Samy Suissa, PhD, from the Center for Clinical Epidemiology, Lady Davis Research Institute, Jewish General Hospital in Montreal, Quebec, Canada, and the Department of Epidemiology and Biostatistics and Department of Medicine, McGill University, said in a news release. "Therefore, patients instituting therapy with high doses of inhaled corticosteroids should be assessed for possible hyperglycemia and treatment with high doses of inhaled corticosteroids [should be] limited to situations where the benefit is clear."
The study authors note that although inhaled corticosteroids are recommended only for patients with the most severe COPD, current practice is that they are prescribed to more than 70% of all patients with COPD, including those with less severe disease. Because the prevalence of COPD and diabetes both increase with age, it is important to examine any possible interaction between inhaled corticosteroid use and worsened glycemic control.
Using the Quebec health insurance databases, the investigators identified a new-user cohort of patients treated from 1990 through 2005 for respiratory disease. Follow-up was through 2007, until diabetes onset, or until diabetes progression in the subcohort treated with oral hypoglycemics. To estimate the rate ratios of diabetes onset and progression associated with current use of inhaled corticosteroids, the investigators used a nested case-control analysis, with adjustment for age, sex, respiratory disease severity, and comorbid conditions.
Of 388,584 patients in the study cohort, 30,167 developed incident diabetes during 5.5 years of follow-up (incidence rate, 14.2/1000/year), and 2099 patients subsequently progressed from oral hypoglycemic therapy to insulin treatment (incidence rate, 19.8/1000/year).
Participants with current use of inhaled corticosteroids had a 34% increase in the rate of diabetes (rate ratio [RR], 1.34; 95% confidence interval [CI], 1.29 - 1.39) and in the rate of diabetes progression (RR, 1.34; 95% CI, 1.17 - 1.53).
The highest inhaled corticosteroid doses, equivalent to at least 1000 μg/day fluticasone, were associated with the greatest risk increases (RR for rate of diabetes, 1.64; 95% CI, 1.52 - 1.76; RR for diabetes progression, 1.54; 95% CI, 1.18 - 2.02).
Limitations of this study include possible residual confounding and the possible underestimation of incidence of diabetes.
"In patients with respiratory disease, inhaled corticosteroid use is associated with modest increases in the risks of diabetes onset and diabetes progression," the study authors write. "The risks are more pronounced at the higher doses currently prescribed in the treatment of [COPD]."
This research was supported by grants from the Canadian Institutes of Health Research, Boehringer-Ingelheim GmbH, and the Canadian Foundation for Innovation. Some of the study authors report various financial relationships with AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Merck, Pfizer, Merck Frosst Canada, Novartis, and/or Nycomed.
Am J Med. 2010;123:1001-1006. Abstract
Montelukast used to treat asthma has been linked to severe CNS reactions, including suicide ideation and self harm. http://www.leaderpost.com/news/Asthma+drug+linked+suicide+attempts+thoughts+self+harm/1768232/story.html
The article below, concerns inhaled corticosteroid and Diabetes Mellitus.
Inhaled Corticosteroid Use May Increase Risk for Diabetes Mellitus
Laurie Barclay, MD
December 15, 2010 — Inhaled corticosteroid use may increase the risk for diabetes mellitus, according to the results of a study reported in the November issue of the American Journal of Medicine.
"High doses of inhaled corticosteroids commonly used in patients with [chronic obstructive pulmonary disease (COPD)] are associated with an increase in the risk of requiring treatment for diabetes and of having to intensify therapy to include insulin," lead author Samy Suissa, PhD, from the Center for Clinical Epidemiology, Lady Davis Research Institute, Jewish General Hospital in Montreal, Quebec, Canada, and the Department of Epidemiology and Biostatistics and Department of Medicine, McGill University, said in a news release. "Therefore, patients instituting therapy with high doses of inhaled corticosteroids should be assessed for possible hyperglycemia and treatment with high doses of inhaled corticosteroids [should be] limited to situations where the benefit is clear."
The study authors note that although inhaled corticosteroids are recommended only for patients with the most severe COPD, current practice is that they are prescribed to more than 70% of all patients with COPD, including those with less severe disease. Because the prevalence of COPD and diabetes both increase with age, it is important to examine any possible interaction between inhaled corticosteroid use and worsened glycemic control.
Using the Quebec health insurance databases, the investigators identified a new-user cohort of patients treated from 1990 through 2005 for respiratory disease. Follow-up was through 2007, until diabetes onset, or until diabetes progression in the subcohort treated with oral hypoglycemics. To estimate the rate ratios of diabetes onset and progression associated with current use of inhaled corticosteroids, the investigators used a nested case-control analysis, with adjustment for age, sex, respiratory disease severity, and comorbid conditions.
Of 388,584 patients in the study cohort, 30,167 developed incident diabetes during 5.5 years of follow-up (incidence rate, 14.2/1000/year), and 2099 patients subsequently progressed from oral hypoglycemic therapy to insulin treatment (incidence rate, 19.8/1000/year).
Participants with current use of inhaled corticosteroids had a 34% increase in the rate of diabetes (rate ratio [RR], 1.34; 95% confidence interval [CI], 1.29 - 1.39) and in the rate of diabetes progression (RR, 1.34; 95% CI, 1.17 - 1.53).
The highest inhaled corticosteroid doses, equivalent to at least 1000 μg/day fluticasone, were associated with the greatest risk increases (RR for rate of diabetes, 1.64; 95% CI, 1.52 - 1.76; RR for diabetes progression, 1.54; 95% CI, 1.18 - 2.02).
Limitations of this study include possible residual confounding and the possible underestimation of incidence of diabetes.
"In patients with respiratory disease, inhaled corticosteroid use is associated with modest increases in the risks of diabetes onset and diabetes progression," the study authors write. "The risks are more pronounced at the higher doses currently prescribed in the treatment of [COPD]."
This research was supported by grants from the Canadian Institutes of Health Research, Boehringer-Ingelheim GmbH, and the Canadian Foundation for Innovation. Some of the study authors report various financial relationships with AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Merck, Pfizer, Merck Frosst Canada, Novartis, and/or Nycomed.
Am J Med. 2010;123:1001-1006. Abstract
Tuesday, December 14, 2010
Friday, December 10, 2010
Published papers show limitations of scans, MRIs, ionic x-rays, contrast dyes, causing side effects. The latter, lists strokes, heart attacks, angina as possible side effects. Galdolinium, commonly used contrast dye is known to cause to nephrogenic fibrosing dermopathy (NFC). Apparently, it can appear even five years later. Reports of many with healthy kidneys prior to being administered contrast dye, complain of sub optimal functioning kidneys, some of failing kidneys, others of angina, chest pains, and heart attacks.
Below is a paper showing scans causing disturbance in the blood brain barrier, linking bleeding/strokes to scan as well as causing damage to the endothelial cells.
Blood-Brain Barrier Disruption By Low-Frequency Ultrasound
Matthias Reinhard, MD; Andreas Hetzel, MD; Sebastian Krüger, MD; Stefan Kretzer, MD; Jochen Talazko, MD; Sargon Ziyeh, MD; Johannes Weber, MD Thomas Els, MD
From the Department of Neurology (M.R., A.H., S. Krüger, S. Kretzer, T.E.); the Department of Nuclear Medicine (J.T.); and the Department of Neuroradiology (S.Z., J.W.), University of Freiburg, Germany.
Correspondence to Andreas Hetzel, MD, Department of Neurology and Clinical Neurophysiology, University of Freiburg, Neurocenter, Breisacherstr. 64, D-79106 Freiburg, Germany. E-mail andreas.hetzel@uniklinik-freiburg.de
Abstract
Background and Purpose— A recent study showed a dramatic increase in cerebral hemorrhage comprising atypical locations with low-frequency ultrasound–mediated recombinant tissue plasminogen activator–thrombolysis in humans. Here, we provide a possible explanation for this phenomenon by a side effect observed in a study using the similar ultrasound device.
Methods— The study was originally undertaken to investigate by transcranial Doppler sonography, positron emission tomography and perfusion MRI whether transcranial application of wide-field low-frequency ultrasound (300 kHz) improves cerebral hemodynamics in patients with cerebral small vessel disease.
Results— Showing no clear positive effect on cerebral hemodynamics in 4 patients and on cerebral perfusion (positron emission tomography) in 2 patients, the study has been terminated early because of a remarkable side effect in the first patient (a 62 year-old man) undergoing perfusion-MRI: detection of frontoparietal extravasation of Gadolinium contrast agent (applied during MRI perfusion imaging preinsonation) on MRI immediately postinsonation.
Conclusions— Abnormal permeability of the human blood-brain barrier can be induced by wide-field low-frequency insonation. The observed excessive bleeding rate with low-frequency sonothrombolysis might thus be attributable to primary blood-brain barrier disruption by ultrasound.
Key Words: blood-brain barrier • hemodynamic phenomena • leukoaraiosis • side effect • ultrasound
http://stroke.ahajournals.org/cgi/content/full/37/6/1546
Below is a paper showing scans causing disturbance in the blood brain barrier, linking bleeding/strokes to scan as well as causing damage to the endothelial cells.
Blood-Brain Barrier Disruption By Low-Frequency Ultrasound
Matthias Reinhard, MD; Andreas Hetzel, MD; Sebastian Krüger, MD; Stefan Kretzer, MD; Jochen Talazko, MD; Sargon Ziyeh, MD; Johannes Weber, MD Thomas Els, MD
From the Department of Neurology (M.R., A.H., S. Krüger, S. Kretzer, T.E.); the Department of Nuclear Medicine (J.T.); and the Department of Neuroradiology (S.Z., J.W.), University of Freiburg, Germany.
Correspondence to Andreas Hetzel, MD, Department of Neurology and Clinical Neurophysiology, University of Freiburg, Neurocenter, Breisacherstr. 64, D-79106 Freiburg, Germany. E-mail andreas.hetzel@uniklinik-freiburg.de
Abstract
Background and Purpose— A recent study showed a dramatic increase in cerebral hemorrhage comprising atypical locations with low-frequency ultrasound–mediated recombinant tissue plasminogen activator–thrombolysis in humans. Here, we provide a possible explanation for this phenomenon by a side effect observed in a study using the similar ultrasound device.
Methods— The study was originally undertaken to investigate by transcranial Doppler sonography, positron emission tomography and perfusion MRI whether transcranial application of wide-field low-frequency ultrasound (300 kHz) improves cerebral hemodynamics in patients with cerebral small vessel disease.
Results— Showing no clear positive effect on cerebral hemodynamics in 4 patients and on cerebral perfusion (positron emission tomography) in 2 patients, the study has been terminated early because of a remarkable side effect in the first patient (a 62 year-old man) undergoing perfusion-MRI: detection of frontoparietal extravasation of Gadolinium contrast agent (applied during MRI perfusion imaging preinsonation) on MRI immediately postinsonation.
Conclusions— Abnormal permeability of the human blood-brain barrier can be induced by wide-field low-frequency insonation. The observed excessive bleeding rate with low-frequency sonothrombolysis might thus be attributable to primary blood-brain barrier disruption by ultrasound.
Key Words: blood-brain barrier • hemodynamic phenomena • leukoaraiosis • side effect • ultrasound
http://stroke.ahajournals.org/cgi/content/full/37/6/1546
Thursday, December 9, 2010
An excellent article in regards to grapefruit and CYPs 450. Many are unable to eat grapefruits following ADRs from Lariam, Fqs and other meds. Watch out if you are on meds. It is important to avoid grapefruit to avoid potentiating and toxicity. Read up on tangerines, mandarines, clementines, oranges.
Mechanism of Grapefruit Juice Interactions
Basic Mechanism of Action
Drugs that interact with grapefruit and/or grapefruit juice (GJ) undergo cytochrome p450 oxidative metabolism in the intestinal wall or liver. GJ contains various furanocoumarins which have been demonstrated to affect the cytochrome p450(CYP) system (especially at isoenzyme CYP3A4) by binding to the isoenzyme as a substrate and impairing first-pass metabolism, by direct inactivation or inhibition of the enzyme (mechanism-based inhibitors). The net effect on the CYP enzymes from this inhibition seems to be a selective down-regulation of CYP3A4 in the small intestine.26 For certain drugs which are known to be CYP 3A4 metabolized, less drug is metabolized prior to absorption, and greater amounts of these drugs reach the systemic circulation, leading to higher blood levels, and potentially to increases in therapeutic and/or toxic effects.
Naringin
Naringin is the main bioflavonoid in GJ. Naringin is not a potent CYP inhibitor, but is partially metabolized by enteral bacteria to naringenin, which is a potent inhibitor of p450 enzymes, and early research into GJ interactions proposed that naringin was the component of GJ responsible for the interactions,4-6 although it was thought possible that another unidentified component in grapefruit may also have been responsible, since giving naringin alone does not seem to cause the same degree of inhibition as GJ.4-5,21 Recent evidence clearly indicate that furanocoumarins, especially dihydroxybergamottin are the chemicals responsible for GJ interactions.
Furanocoumarins/Dihydroxybergamottin
Researchers have isolated a group of compounds from GJ called furanocoumarins, which appear to be specific CYP3A4 inhibitors.27-29 A study on extracts of GJ interacting with rat and human p450 found that naringin accounted for only 10% of the inhibition of CYP activity seen with GJ.28 In vitro results show that a compound known as 6',7'-dihydroxybergamottin may be the chemical which accounts for the difference in effects on CYP3A substrates caused by GJ versus naringenin.27 A separate study with in vitro data determined that several compounds found in GJ inhibit CYP3A4 enzymes. Specifically, these were nootkanone (a sesquiterpene), and 4 derivatives of coumarin, geranyloxycoumarin, bergamottin, and 2 chemical with very long technical names, denoted as GF-I-1 and 4.29 Additional CYP3A inhibitory chemicals GF-I-5, GF-I-6 and bergapten have also been identified.132 The concentrations of nootkanone and bergamottin required to inhibit CYP3A4 enzymes however, was found to be higher than the naturally occurring concentrations found in GJ.
Results of confirmatory in vivo testing of CYP3A4 inhibition with externally administered GF-I-1, GF-I-4, GF-I-5 and GF-I-6 have not been published at present. It should also be noted that wide inter-individual variability in response to these interactions have been documented in studies.2,11
Start of New Article A recent study determined that the chemical moiety 5-geranyloxyfurocoumarine is essential for CYP3A4 inhibitory activity. This moiety is found in dihydroxybergamottin, as well as GF-I-1 and GF-I-4.127 A total of 6 furanocoumarin derivatives are suggested to be clinically active constituents of GJ.129
Commercial manufacturing of GJ is a multi-step process that includes washing of unpeeled fruit prior to squeezing whole fruits to juice. After squeezing, juice is heated for pasteurization, and volatile components may evaporate. Grapefruit oil, an important constituent of grapefruit peel, is sometimes added to the concentrate as a flavor enhancer.
A study found that epoxybergamottin, a furanocoumarin extracted from grapefruit peel is also an inhibitor of CYP 3A4. This compound has previously been found in only minor quantities in GJ, compared to 6'7'-dihydroxybergamottin. The authors note that it is possible that this compound could be distributed into the juice, during the commercial juice manufacturing process. Epoxybergamottin is not chemically stable in acidic medium, and may become hydrolyzed to 6'7'-dihydroxybergamottin.134
P-glycoprotein
A study performed in cellular models indicates that GJ significantly activates p-glycoprotein mediated reduction in bioavailability, partially counteracting the CYP3A4 inhibitory effects of GJ.42 This experiment was performed in laboratory (CaCo-2) cell cultures, and was not a human trial. The results of this experiment were later found to be due to a laboratory artifact and were retracted132, though the retraction was not published by the original author. Subsequent results indicate that GJ likely acts as a weak p-glycoprotein inhibitor.
Start of New ArticleA recent study using GJ and digoxin shed further light on p-glycoprotein effects in humans. In a randomized crossover fashion, 12 healthy volunteers (7 male, 5 female) were given a single oral dose of digoxin 0.5 mg with either water or 250 mL of SSGJ 30 minutes prior to the dose, and 3.5, 7.5 and 11.5 hours after the dose. A two-week washout between study periods was employed.
Compared to the water group, mean peak blood concentrations (Cmax) rose 21%, time to peak level (Tmax) rose 8%, and total drug exposure at 48 hours (AUC48) rose 9%. None of these changes were statistically significant. AUC at 4 and 24 hours also rose 9% and this was considered statistically significant.
The authors consider GJ a weak inhibitor of P-glycoprotein, since studies with other known P-glycoprotein inhibitors show larger increases in digoxin AUC. They concluded that the study did not support the role of GJ as an important P-glycoprotein inhibitor, and that the modest increases in digoxin concentrations observed did not require any recommendations to alter digoxin dosing or titration when taken with GJ.114
Start of New ArticleIn a similar study, 7 healthy volunteers (4 male, 3 female) received a single oral dose of digoxin 1 mg with with either water or GJ in a randomized crossover design. A washout of two weeks between study periods was employed.
During the GJ phase, 240 mL of SSGJ was consumed 3 times daily for 5 days prior to digoxin administration, and 6 days after digoxin administration, in an attempt to maximize the effect on p-glycoprotein.
Compared to water, administration of digoxin with GJ showed peak blood levels (Cmax) decreased by a mean of 16%, total drug exposure (AUC) increased 3%, Time to peak concentration (Tmax) increased 25% and half-life was essentially unchanged (decreased by 3%). None of these changes were determined to be statistically significant, although significant interindividual variability was observed.
The authors concluded that when results are taken with the previous study, GJ ingestion does not have a significant effect on intestinal P-glycoprotein activity, and that P-glycoprotein inhibition does not play an important role in grapefruit interactions.115
Seville Orange Juice
Start of New ArticleA trial of administration of cyclosporine with GJ and Seville orange juice, both of which contain 6',7'-dihydroxybergamottin, was conducted recently. 7 healthy volunteers were given either water, single-strength GJ, or Seville orange juice 30 minutes prior to a 7.5 mg/kg dose of cyclosporine (Sandimmune® brand) in a randomized crossover design. The effect of Seville orange juice on CYP 3A4 concentrations in 2 individuals (via duodenal biopsy) and the effect of 6',7'-dighydroxybergamottin on p-glycoprotein activity in vitro were also assessed. The AUC for cyclosporine was increased 55% with GJ, whereas Seville orange juice did no significantly affect the AUC of cyclosporine. The two individuals who had duodenal biopsy showed clearly decreased enterocyte concentrations of CYP 3A4, suggesting that 6',7'-dihydroxybergamottin is not solely responsible for the increased cyclosporine levels when given with GJ. The in vitro studies confirmed that 6',7'-dihydroxybergamottin had no effect on p-glycoprotein.
So, if the two juices had similar concentrations of 6',7'-dihydroxybergamottin, why did cyclosporine blood levels increase with GJ, but not with Seville orange juice ? P-glycoprotein is known to play a significant role in cyclosporine availability, and based on this study, and in agreement with the study listed above, it is reasonable to conclude that GJ contains a compound or compounds that inhibit P-glycoprotein activity, which are not found in Seville oranges. Further studies are needed to identify inhibitors of p-glycoprotein in GJ and to evaluate the relative contribution of reduced p-glycoprotein and CYP 3A4 activity to the increased oral bioavailability of other drugs.51 Seville oranges may selectively "knock out" CYP 3A4 activity, while the inhibitor(s) of p-glycoprotein in GJ appear to be different from those compounds identified as inactivating CYP 3A4.132
Start of New ArticleEleven healthy volunteers (6 male, 5 female) received 30mg dextromethorphan daily for 5 days with either 200 mL single-strength GJ (study day 2), 200 mL seville orange juice (SOJ) (study day 4), or water (study day 1, 3, 5) in a linear, non-crossover fashion. Immediately, the non-crossover design raises a concern, since the effect of GJ on the enzymes is known to persist for 72 hours or more. A 3 -day washout was given after study day 2, and at least 7-days passed between study day 2 and 4. Blood levels were not collected in this study. Urine point assays, and 8-hour total urine concentrations were used to determine dextromethorphan availability in a complicated series of analyses, based partially on animal data, and some assumptions.
The fraction of the administered dose of dextromethorphan that escaped first pass metabolism were found to increase significantly and similarly when GJ or SOJ were taken with dextromethorphan on study days 2 and 4, although lack of an adequate washout period after GJ intake on day 2 was provided, the administration of SOJ with dextromethorphan produced an identical effect on the dextromethorphan pharmacokinetic profile as was observed with GJ. Two volunteers experienced drowsiness, but were found to be CYP 2D6 "poor metabolizers" (the alternate metabolic pathway for dextromethorphan and its metabolites). It also appears that both GJ and SOJ affected p-glycoprotein transport protein activity.94
Start of New ArticleTen healthy volunteers (5 male, 5 female) received a dose of felodipine 10mg with 240 mL of either fresh squeezed Seville orange juice, commercial orange juice, or grapefruit juice (diluted to contain the same total molar concentration of bergamottin and 6'7'-dihydroxybergamottin as the Seville orange juice). This study was conducted in randomized crossover design with at least a 7 day washout between study periods.
Seville orange juice increased felodipine AUC 76% and Cmax was increased 61%, compared to commercial orange juice (control). As expected, grapefruit juice increased felodipine AUC by 83% with Cmax increased 88%
An additional CYP 3A4 inhibitor, bergapten was found in seville orange juice, but not in grapefruit juice. Bergapten appears to have 1/3 the potency of 6'7'-dihydroxybergamottin when tested with midazolam in intestinal cell concentrations.132
Pomelo & Other Related Citrus Fruits
Start of New ArticleA case report exists of an interaction between tacrolimus and pomelo (also known as pummelo), a grapefruit-related citrus fruit. A patient taking tacrolimus post-renal transplant was stabilized on a tacrolimus dosage of 6 mg/day with tacrolimus blood levels stable in the therapeutic range of 8-10 ng/mL. A subsequent check of the tacrolimus level was increased at 25.2 ng/mL. The patient had no subjective symptoms. Upon further questioning, it was revealed that he had consumed approximately 100g of pomelo from his garden just prior to the tacrolimus on the day before blood sampling for tacrolimus level determination.117
Start of New ArticleFollow up testing by the above authors confirmed that some forms (1 of 3 tested) of pomelo juice extract were as potent inhibitors of CYP 3A4 as grapefruit juice extract in vitro. The pomelo extract had little effect on p-glycoprotein in a cellular model.124
Start of New ArticleIn 2004, Japanese researchers developed an enzyme-linked immunosorbent assay specific for coumarin derivatives that contain the geranyloxy- side chain, known to be the chemical moiety in grapefruit responsible for CYP3A4 inhibition. This allowed other fruits to be screened for containing 6'7'-dihydroxybergamottin.
Of 15 fruits screened, white grapefruit (control), red pummelo (pomelo), sweetie (oro blanco), melogold, banpeiyu pummelo, hassaku orange, sour (seville) orange, lime and natsudaidai showed significant immunoreactivity, indicating the presence of furanocoumarin derivatives. Navel orange, sweet orange and yuzu showed slight immunoreactivity, while iyokan orange, satsuma mandarin, ponkan mandarin and dekopon mandarin showed minimal immunoreactivity.
The researchers noted that besides the Rutaceae family (grapefruit-like) many plants of other families such as Umbelliferae, Leguminosae and Moraceae also contain furanocoumarin derivatives. Many plants of these families are used as common vegetables or traditional medicines, and it is possible that furanocoumarin derivatives contained in these plants could change the pharmacokinetics of certain drugs.129
Start of New ArticleIn a related study, Japanese researchers performed in vitro testing of local citrus fruits by incubating citrus fruit residue with human liver extract, midazolam, and measuring residual CYP 3A activity. Fruit juice residues prepared from banpeiyu pummelo, hassaku orange, takaoka-(suisho) buntan pummelo and kinkan (Tamatama) inhibited microsomal CYP 3A activity. Banpeiyu pummelo inhibition was strongest, though weaker than the white grapefruit control. No significant CYP 3A inhibition was noted with ama-natsu orange, dekopon mandarin, hyuga-natsu orange, unshu-mikan (satsuma mandarin) or navel orange. These findings are in agreement with the above study which looked at enzyme-linked immunoreactivity testing.130
Start of New Article In another related study by Japanese researchers, in vitro testing of tropical fruits was performed by incubating citrus fruit residue with human liver extract, midazolam, and measuring residual CYP 3A activity. Residues prepared from star fruit, pomegranate, and common papaw significantly inhibited CYP 3A activity. In all three cases, inhibition was stronger than the white grapefruit control. No significant inhibition was noted with valencia orange, mango, rambutan, kiwi fruit, dragon fruit or passion fruit.131
Time course of GJ-drug Interactions
Start of New ArticleA research group conducted a study with simvastatin to characterize the duration of the GJ induced CYP 3A4 inhibition. Ten healthy volunteers (9 male, 1 female) received simvastatin 40 mg with either water as a control, and either 0, 1, 3 or 7 days after drinking high-dose GJ (200 mL double-strength GJ) three times daily for 3 days in a non-randomized crossover fashion. As seen with the previous study, significant increases in simvastatin levels after GJ intake were observed on the day 0 study when compared with water. Simvastatin AUC was increased 1250%, with Cmax increased 1104%. Time to peak concentration (Tmax) was also prolonged from 2 hours to 4 hours (100% increase). This effect was significantly reduced if 24 hours elapsed between the last GJ intake and simvastatin dosing. At this time, simvastatin AUC was increased 105%, and Cmax was increased 136%. The authors noted that the effect of even high-dose GJ 24 hours after ingestion is only about 10% of that seen with concurrent GJ and simvastatin intake. AUC and Cmax of simvastatin when taken on day 3 and day 7 after last GJ intake were not significantly elevated compared to control, indicating that the interaction potential of even high amounts of GJ intake dissipates within 3-7 days after last GJ ingestion.
This is useful for characterizing the time course of GJ-drug interactions, and fits with prior expectations that the GJ effect can last up to 3 days after last GJ ingestion.90
Cont/... http://www.powernetdesign.com/grapefruit/general/mechanism.html
Mechanism of Grapefruit Juice Interactions
Basic Mechanism of Action
Drugs that interact with grapefruit and/or grapefruit juice (GJ) undergo cytochrome p450 oxidative metabolism in the intestinal wall or liver. GJ contains various furanocoumarins which have been demonstrated to affect the cytochrome p450(CYP) system (especially at isoenzyme CYP3A4) by binding to the isoenzyme as a substrate and impairing first-pass metabolism, by direct inactivation or inhibition of the enzyme (mechanism-based inhibitors). The net effect on the CYP enzymes from this inhibition seems to be a selective down-regulation of CYP3A4 in the small intestine.26 For certain drugs which are known to be CYP 3A4 metabolized, less drug is metabolized prior to absorption, and greater amounts of these drugs reach the systemic circulation, leading to higher blood levels, and potentially to increases in therapeutic and/or toxic effects.
Naringin
Naringin is the main bioflavonoid in GJ. Naringin is not a potent CYP inhibitor, but is partially metabolized by enteral bacteria to naringenin, which is a potent inhibitor of p450 enzymes, and early research into GJ interactions proposed that naringin was the component of GJ responsible for the interactions,4-6 although it was thought possible that another unidentified component in grapefruit may also have been responsible, since giving naringin alone does not seem to cause the same degree of inhibition as GJ.4-5,21 Recent evidence clearly indicate that furanocoumarins, especially dihydroxybergamottin are the chemicals responsible for GJ interactions.
Furanocoumarins/Dihydroxybergamottin
Researchers have isolated a group of compounds from GJ called furanocoumarins, which appear to be specific CYP3A4 inhibitors.27-29 A study on extracts of GJ interacting with rat and human p450 found that naringin accounted for only 10% of the inhibition of CYP activity seen with GJ.28 In vitro results show that a compound known as 6',7'-dihydroxybergamottin may be the chemical which accounts for the difference in effects on CYP3A substrates caused by GJ versus naringenin.27 A separate study with in vitro data determined that several compounds found in GJ inhibit CYP3A4 enzymes. Specifically, these were nootkanone (a sesquiterpene), and 4 derivatives of coumarin, geranyloxycoumarin, bergamottin, and 2 chemical with very long technical names, denoted as GF-I-1 and 4.29 Additional CYP3A inhibitory chemicals GF-I-5, GF-I-6 and bergapten have also been identified.132 The concentrations of nootkanone and bergamottin required to inhibit CYP3A4 enzymes however, was found to be higher than the naturally occurring concentrations found in GJ.
Results of confirmatory in vivo testing of CYP3A4 inhibition with externally administered GF-I-1, GF-I-4, GF-I-5 and GF-I-6 have not been published at present. It should also be noted that wide inter-individual variability in response to these interactions have been documented in studies.2,11
Start of New Article A recent study determined that the chemical moiety 5-geranyloxyfurocoumarine is essential for CYP3A4 inhibitory activity. This moiety is found in dihydroxybergamottin, as well as GF-I-1 and GF-I-4.127 A total of 6 furanocoumarin derivatives are suggested to be clinically active constituents of GJ.129
Commercial manufacturing of GJ is a multi-step process that includes washing of unpeeled fruit prior to squeezing whole fruits to juice. After squeezing, juice is heated for pasteurization, and volatile components may evaporate. Grapefruit oil, an important constituent of grapefruit peel, is sometimes added to the concentrate as a flavor enhancer.
A study found that epoxybergamottin, a furanocoumarin extracted from grapefruit peel is also an inhibitor of CYP 3A4. This compound has previously been found in only minor quantities in GJ, compared to 6'7'-dihydroxybergamottin. The authors note that it is possible that this compound could be distributed into the juice, during the commercial juice manufacturing process. Epoxybergamottin is not chemically stable in acidic medium, and may become hydrolyzed to 6'7'-dihydroxybergamottin.134
P-glycoprotein
A study performed in cellular models indicates that GJ significantly activates p-glycoprotein mediated reduction in bioavailability, partially counteracting the CYP3A4 inhibitory effects of GJ.42 This experiment was performed in laboratory (CaCo-2) cell cultures, and was not a human trial. The results of this experiment were later found to be due to a laboratory artifact and were retracted132, though the retraction was not published by the original author. Subsequent results indicate that GJ likely acts as a weak p-glycoprotein inhibitor.
Start of New ArticleA recent study using GJ and digoxin shed further light on p-glycoprotein effects in humans. In a randomized crossover fashion, 12 healthy volunteers (7 male, 5 female) were given a single oral dose of digoxin 0.5 mg with either water or 250 mL of SSGJ 30 minutes prior to the dose, and 3.5, 7.5 and 11.5 hours after the dose. A two-week washout between study periods was employed.
Compared to the water group, mean peak blood concentrations (Cmax) rose 21%, time to peak level (Tmax) rose 8%, and total drug exposure at 48 hours (AUC48) rose 9%. None of these changes were statistically significant. AUC at 4 and 24 hours also rose 9% and this was considered statistically significant.
The authors consider GJ a weak inhibitor of P-glycoprotein, since studies with other known P-glycoprotein inhibitors show larger increases in digoxin AUC. They concluded that the study did not support the role of GJ as an important P-glycoprotein inhibitor, and that the modest increases in digoxin concentrations observed did not require any recommendations to alter digoxin dosing or titration when taken with GJ.114
Start of New ArticleIn a similar study, 7 healthy volunteers (4 male, 3 female) received a single oral dose of digoxin 1 mg with with either water or GJ in a randomized crossover design. A washout of two weeks between study periods was employed.
During the GJ phase, 240 mL of SSGJ was consumed 3 times daily for 5 days prior to digoxin administration, and 6 days after digoxin administration, in an attempt to maximize the effect on p-glycoprotein.
Compared to water, administration of digoxin with GJ showed peak blood levels (Cmax) decreased by a mean of 16%, total drug exposure (AUC) increased 3%, Time to peak concentration (Tmax) increased 25% and half-life was essentially unchanged (decreased by 3%). None of these changes were determined to be statistically significant, although significant interindividual variability was observed.
The authors concluded that when results are taken with the previous study, GJ ingestion does not have a significant effect on intestinal P-glycoprotein activity, and that P-glycoprotein inhibition does not play an important role in grapefruit interactions.115
Seville Orange Juice
Start of New ArticleA trial of administration of cyclosporine with GJ and Seville orange juice, both of which contain 6',7'-dihydroxybergamottin, was conducted recently. 7 healthy volunteers were given either water, single-strength GJ, or Seville orange juice 30 minutes prior to a 7.5 mg/kg dose of cyclosporine (Sandimmune® brand) in a randomized crossover design. The effect of Seville orange juice on CYP 3A4 concentrations in 2 individuals (via duodenal biopsy) and the effect of 6',7'-dighydroxybergamottin on p-glycoprotein activity in vitro were also assessed. The AUC for cyclosporine was increased 55% with GJ, whereas Seville orange juice did no significantly affect the AUC of cyclosporine. The two individuals who had duodenal biopsy showed clearly decreased enterocyte concentrations of CYP 3A4, suggesting that 6',7'-dihydroxybergamottin is not solely responsible for the increased cyclosporine levels when given with GJ. The in vitro studies confirmed that 6',7'-dihydroxybergamottin had no effect on p-glycoprotein.
So, if the two juices had similar concentrations of 6',7'-dihydroxybergamottin, why did cyclosporine blood levels increase with GJ, but not with Seville orange juice ? P-glycoprotein is known to play a significant role in cyclosporine availability, and based on this study, and in agreement with the study listed above, it is reasonable to conclude that GJ contains a compound or compounds that inhibit P-glycoprotein activity, which are not found in Seville oranges. Further studies are needed to identify inhibitors of p-glycoprotein in GJ and to evaluate the relative contribution of reduced p-glycoprotein and CYP 3A4 activity to the increased oral bioavailability of other drugs.51 Seville oranges may selectively "knock out" CYP 3A4 activity, while the inhibitor(s) of p-glycoprotein in GJ appear to be different from those compounds identified as inactivating CYP 3A4.132
Start of New ArticleEleven healthy volunteers (6 male, 5 female) received 30mg dextromethorphan daily for 5 days with either 200 mL single-strength GJ (study day 2), 200 mL seville orange juice (SOJ) (study day 4), or water (study day 1, 3, 5) in a linear, non-crossover fashion. Immediately, the non-crossover design raises a concern, since the effect of GJ on the enzymes is known to persist for 72 hours or more. A 3 -day washout was given after study day 2, and at least 7-days passed between study day 2 and 4. Blood levels were not collected in this study. Urine point assays, and 8-hour total urine concentrations were used to determine dextromethorphan availability in a complicated series of analyses, based partially on animal data, and some assumptions.
The fraction of the administered dose of dextromethorphan that escaped first pass metabolism were found to increase significantly and similarly when GJ or SOJ were taken with dextromethorphan on study days 2 and 4, although lack of an adequate washout period after GJ intake on day 2 was provided, the administration of SOJ with dextromethorphan produced an identical effect on the dextromethorphan pharmacokinetic profile as was observed with GJ. Two volunteers experienced drowsiness, but were found to be CYP 2D6 "poor metabolizers" (the alternate metabolic pathway for dextromethorphan and its metabolites). It also appears that both GJ and SOJ affected p-glycoprotein transport protein activity.94
Start of New ArticleTen healthy volunteers (5 male, 5 female) received a dose of felodipine 10mg with 240 mL of either fresh squeezed Seville orange juice, commercial orange juice, or grapefruit juice (diluted to contain the same total molar concentration of bergamottin and 6'7'-dihydroxybergamottin as the Seville orange juice). This study was conducted in randomized crossover design with at least a 7 day washout between study periods.
Seville orange juice increased felodipine AUC 76% and Cmax was increased 61%, compared to commercial orange juice (control). As expected, grapefruit juice increased felodipine AUC by 83% with Cmax increased 88%
An additional CYP 3A4 inhibitor, bergapten was found in seville orange juice, but not in grapefruit juice. Bergapten appears to have 1/3 the potency of 6'7'-dihydroxybergamottin when tested with midazolam in intestinal cell concentrations.132
Pomelo & Other Related Citrus Fruits
Start of New ArticleA case report exists of an interaction between tacrolimus and pomelo (also known as pummelo), a grapefruit-related citrus fruit. A patient taking tacrolimus post-renal transplant was stabilized on a tacrolimus dosage of 6 mg/day with tacrolimus blood levels stable in the therapeutic range of 8-10 ng/mL. A subsequent check of the tacrolimus level was increased at 25.2 ng/mL. The patient had no subjective symptoms. Upon further questioning, it was revealed that he had consumed approximately 100g of pomelo from his garden just prior to the tacrolimus on the day before blood sampling for tacrolimus level determination.117
Start of New ArticleFollow up testing by the above authors confirmed that some forms (1 of 3 tested) of pomelo juice extract were as potent inhibitors of CYP 3A4 as grapefruit juice extract in vitro. The pomelo extract had little effect on p-glycoprotein in a cellular model.124
Start of New ArticleIn 2004, Japanese researchers developed an enzyme-linked immunosorbent assay specific for coumarin derivatives that contain the geranyloxy- side chain, known to be the chemical moiety in grapefruit responsible for CYP3A4 inhibition. This allowed other fruits to be screened for containing 6'7'-dihydroxybergamottin.
Of 15 fruits screened, white grapefruit (control), red pummelo (pomelo), sweetie (oro blanco), melogold, banpeiyu pummelo, hassaku orange, sour (seville) orange, lime and natsudaidai showed significant immunoreactivity, indicating the presence of furanocoumarin derivatives. Navel orange, sweet orange and yuzu showed slight immunoreactivity, while iyokan orange, satsuma mandarin, ponkan mandarin and dekopon mandarin showed minimal immunoreactivity.
The researchers noted that besides the Rutaceae family (grapefruit-like) many plants of other families such as Umbelliferae, Leguminosae and Moraceae also contain furanocoumarin derivatives. Many plants of these families are used as common vegetables or traditional medicines, and it is possible that furanocoumarin derivatives contained in these plants could change the pharmacokinetics of certain drugs.129
Start of New ArticleIn a related study, Japanese researchers performed in vitro testing of local citrus fruits by incubating citrus fruit residue with human liver extract, midazolam, and measuring residual CYP 3A activity. Fruit juice residues prepared from banpeiyu pummelo, hassaku orange, takaoka-(suisho) buntan pummelo and kinkan (Tamatama) inhibited microsomal CYP 3A activity. Banpeiyu pummelo inhibition was strongest, though weaker than the white grapefruit control. No significant CYP 3A inhibition was noted with ama-natsu orange, dekopon mandarin, hyuga-natsu orange, unshu-mikan (satsuma mandarin) or navel orange. These findings are in agreement with the above study which looked at enzyme-linked immunoreactivity testing.130
Start of New Article In another related study by Japanese researchers, in vitro testing of tropical fruits was performed by incubating citrus fruit residue with human liver extract, midazolam, and measuring residual CYP 3A activity. Residues prepared from star fruit, pomegranate, and common papaw significantly inhibited CYP 3A activity. In all three cases, inhibition was stronger than the white grapefruit control. No significant inhibition was noted with valencia orange, mango, rambutan, kiwi fruit, dragon fruit or passion fruit.131
Time course of GJ-drug Interactions
Start of New ArticleA research group conducted a study with simvastatin to characterize the duration of the GJ induced CYP 3A4 inhibition. Ten healthy volunteers (9 male, 1 female) received simvastatin 40 mg with either water as a control, and either 0, 1, 3 or 7 days after drinking high-dose GJ (200 mL double-strength GJ) three times daily for 3 days in a non-randomized crossover fashion. As seen with the previous study, significant increases in simvastatin levels after GJ intake were observed on the day 0 study when compared with water. Simvastatin AUC was increased 1250%, with Cmax increased 1104%. Time to peak concentration (Tmax) was also prolonged from 2 hours to 4 hours (100% increase). This effect was significantly reduced if 24 hours elapsed between the last GJ intake and simvastatin dosing. At this time, simvastatin AUC was increased 105%, and Cmax was increased 136%. The authors noted that the effect of even high-dose GJ 24 hours after ingestion is only about 10% of that seen with concurrent GJ and simvastatin intake. AUC and Cmax of simvastatin when taken on day 3 and day 7 after last GJ intake were not significantly elevated compared to control, indicating that the interaction potential of even high amounts of GJ intake dissipates within 3-7 days after last GJ ingestion.
This is useful for characterizing the time course of GJ-drug interactions, and fits with prior expectations that the GJ effect can last up to 3 days after last GJ ingestion.90
Cont/... http://www.powernetdesign.com/grapefruit/general/mechanism.html
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